Human immunodeficiency virus (HIV) is a prototype for pathogenic human retroviruses (i.e. viruses which utilize reverse transcription to replicate). Reverse transcription refers to a process mediated inside a cell by a viral DNA polymerase which can catalyze the flow of genetic information from RNA to DNA. The knowledge, protocols, and teachings pertaining to the avoidance of neuropathy, pancreatitis, and hepatitis with 2',3'-dideoxyinosine as an anti-HIV agent are useful not only for AIDS-like illnesses, but also for 2',3'-dideoxyinosine-treatable illnesses caused by other human viruses which use wholly or in part reverse transcriptase mechanisms to replicate. This includes HTLV-1, HTLV-2, HTLV-V, HIV-2, and hepatitis B virus.
Human immunodeficiency virus (HIV) infection causes a number of clinical abnormalities that can lead to death. The diseases caused by HIV can be treated by certain drugs, including 3'-azido-2',3'-dideoxythymidine (AZT, zidovudine). However, each therapeutically useful drug may be significantly limited in its therapeutic application in human beings by specific toxicities and side-effects. In this regard, since AZT is the only drug now approved specifically for anti-retroviral therapy, it is worth focusing on AZT by way of introduction. AZT causes anemia, other bone marrow suppression, and certain other toxicities such as myositis (muscle destruction or inflammation), headaches, nausea, vomiting, malaise, or seizures. AZT is not known to cause pancreatitis or a peripheral neuropathy, but can cause hepatic dysfunction. Such toxicities and Side effects of a drug become crucial factors for optimizing therapy when using a given drug.
The toxicities and side effects caused by a drug in human beings cannot reliably be predicted from in vitro or animal (pre-clinical) studies. For certain toxicities, for example neuropathy and pancreatitis, no tissue culture model exists. Also, reliable extrapolation of specific toxicities from one drug to another is not possible for purposes of drug selection or dose optimization. Moreover, Phase I studies in humans using dose-escalating clinical tests to assess toxicity profiles do not provide teachings about long-term toxicities, nor do such Phase I studies disclose how to manage and avoid such toxicities and side-effects. These considerations become particularly important when very long term therapy is contemplated. HIV therapy is now thought to be a life-long process. Thus, while any prolongation of life or alleviation of suffering is important, it is crucial to develop methods for successfully administering new therapies for long periods of time. In addition to our ability to predict acute toxicities, no method for predicting the overall long-term toxicity profile of a new drug currently exists, particularly when the drug is used for very long-term therapy. Also, once a patient develops a toxicity or adverse reaction, there is often no teaching of methods to predict whether the patient may be safely and effectively re-started on the new drug. The physician and patient would then surely be grateful for the clinical improvement up until the time of an adverse reaction, but would not have guidance as to what to do next. Without such teachings, the possibility of a lethal or incapacitating adverse reaction always looms on the horizon. Having the ability to suppress viral replication with minimal toxicities for very long periods represents a significant addition to a physician's armamentarium.
AZT, discussed above, is the only compound approved for antiretroviral therapy, but to date, no curative therapy exists and many patients cannot tolerate long-term AZT therapy. Furthermore, in some patients, disease processes progress in the face of AZT therapy for any of several reasons, possibly including the development of AZT-resistant strains of the AIDS virus. In addition, the overall cost of therapy presents serious challenges in continued use for many patients.
2',3'-Dideoxyinosine is also known to suppress retroviral replication and thereby benefit an infected host, and initial clinical trials have been reported which demonstrate its efficacy. However, there are currently no teachings or protocols which guide the physician in using 2',3'-dideoxyinosine for very long periods of time, or which prevent or ameliorate serious and unpredictable side effects. In addition, no teachings or protocols exist for the use of this drug on a chronic basis for patients who have already developed a side effect due to 2',3'-dideoxyinosine and in whom the physician wishes to suspend and later restart administration of the drug. Moreover, there are no teachings or protocols for long-term use of 2',3'-dideoxyinosine in patients who have failed currently approved therapy, whose strain of human immunodeficiency virus has become resistant to AZT, or who cannot tolerate AZT.
Relevant citations are provided below, the disclosures of which are incorporated herein by reference in their entirety:
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